Research Fellow Daniel Menendez, Ph.D., seemed to ponder the ways Bogenhagen's work intersects with his own in the NIEHS Chromosome Stability Group.
(Photo courtesy of Steve McCaw)

NIEHS DNA Replication Fidelity Group Postdoctoral Fellow Amy Abdulovic, Ph.D., is a member of the LMG Trainee Action Committee, the group that sponsors the speakers' program and the annual LMG retreat.
(Photo courtesy of Steve McCaw)

Kasiviswanathan, above, introduced the speaker and monitored the question-and-answer session following the talk.
(Photo courtesy of Steve McCaw)

The NIEHS Laboratory of Molecular Genetics (LMG) Fellows Invited Guest Lecture series welcomed its latest speaker on March 30 with a talk on "Biogenesis and Heredity" by Dan Bogenhagen, M.D. The talk was hosted by LMG Visiting Fellow Rajesh Kasiviswanathan, Ph.D., a member of the Mitochondrial DNA (mtDNA) Replication Group (http://www.niehs.nih.gov/research/atniehs/labs/lmg/mdnar/index.cfm).

Bogenhagen (http://www.pharm.stonybrook.edu/bogenhagen) is a professor in the Department of Pharmacological Sciences at the State University of New York at Stony Brook. His talk outlined what he called "the slightly different direction" of research in his lab at Stony Brook, with protein-sequencing techniques, and at the Howard Hughes Medical Institute (HHMI) Janelia Farm Research Campus, using super-resolution imaging techniques, to study the mechanisms of nucleoid replication in mitochondria.

Pointing to the "intimate involvement" of mitochondria in the life and death of the cell, Bogenhagen launched his discussion by noting that it is also the only organelle apart from the nucleus that is known to contain DNA. This "compact circular mtDNA genome," he said, is an excellent "complete genetic system" for studying the repair and encoding processes related to mtDNA dysfunction that impacts neurodegeneration, cancer and many other diseases.

As Bogenhagen explained, his central research interests are "how mtDNA is packaged and what the actual molecular environment is for the mitochondrial genome." He said that the mitochondria genome encodes only 13 protein subunits of enzyme complexes - "probably only about one percent of the proteins that work in mitochondria." According to Bogenhagen, the mechanisms involved in mtDNA packaging are not well understood.

"There are probably 200 proteins in the nuclear genome just to support the luxury of having 13 genes controlled in mtDNA," Bogenhagen continued. "In many ways, this may not be a very sensible design... Despite a large investment of resources, it doesn't really work very well - kind of like our banking system." He said that "on a per base-pair basis, mtDNA is one of the most disease-rich DNA regions in our bodies." The inefficiency of repair proteins may make mtDNA especially susceptible to oxidative stress and contribute to polymorphism and human disease, he added.

Bogenhagen discussed studies of animal models - mutated mice and aging non-human primates - that have shown that mitochondrial dysfunction increases with age, accompanied by a loss of muscle mass and an increase in electron-chain abnormalities. He then described unbiased searches for accessory proteins involved in organizing and packaging mtDNA and metabolic proteins that revealed metabolic proteins associated with mtDNA. This work suggested a model in which mtDNA nucleoids function as centers for mitochondrial biogenesis. In collaboration with researchers at the HHMI, he has also tested high-resolution microscopy methods, such as photoactivated localization microscopy (PALM), to produce higher resolution images to help localize nucleoids.

Using the model his lab has developed, Bogenhagen devoted the final part of the lecture to what he conceded was "speculation about what would be the implications... on how mtDNA is managed in the cell." One overriding theme was that "mitochondrial biogenesis is local," leading to the hypothesis that genetic complementation is limited and that nucleoids are stable and remain segregated as they "service their own neighborhoods" to ensure adequate energy production in the mitochondria.

Understanding of the replication, repair and expression of mtDNA, according to Bogenhagen, is important due to the association of mtDNA polymorphism in a growing list of diseases. Mitochondrial DNA mutations have been implicated both in rare genetic diseases and, increasingly, in more common conditions such as Parkinson's disease and type 2 diabetes - diseases that worsen with age, possibly both as a direct cause and as a contributing factor because of the progressive mitochondrial dysfunction observed with advanced aging.

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